Deciding When to Treat Excess Iron

Vinod Pullarkat, MD: The decision to use an iron chelator in MDS is easier in a patient who has a lower-risk IPSS score because those patients are going to live longer. And if they’re transfusion-dependent, it is only a matter of time before iron overload sets in. The risk/benefit ratio in that patient favors iron chelation. Preventing iron overload in that patient would have important benefits with regard to long-term complications. If that patient was to require a stem cell transplant later on, the complications would be less. So, in that situation, although the patient may experience some side defects from the chelator itself, the benefits would clearly outweigh the risks.

In a higher-risk patient, we do not have enough data about the benefits of chelation. But, as more and more data accumulate, if there is a survival advantage and if there is delay in leukemic transformation, again, one could accept the risks of the treatment itself or the side effects if the survival is improved or if leukemic transformation is delayed. So, the important considerations would be the risk of the patient. Other comorbidities are important. For example, if you have renal dysfunction, using a chelator like deferasirox would obviously be difficult. And these patients often do have a lot of comorbidities. These are important considerations in deciding to use the drug.

Heather Leitch, MD, PhD: In terms of when to initiate iron chelation therapy, this is often dictated by the reimbursing authorities; for example, in British Columbia where I live. And their criteria are based on the data from congenital anemia. So, for example, a transfusion threshold of 20 red blood cell units, there’s a serum ferritin threshold of over 1000. I think we still have a lot to learn about MDS and whether these thresholds are appropriate. But what I will say is that in a substantial minority of patients, you may run into side effects that will limit the dose that you can give these patients. And so, whether it’s GI side effects or whether it’s an increase in creatinine levels, that can really limit the amount of iron that you can offload. I think that makes more sense moving forward and looking into the future to look at trying to use iron chelation therapy to prevent significant iron overload than trying to catch up with damaged tissue and organs.

Thomas Prebet, MD, PhD: When we assess the need for an iron chelation agent in patients with myelodysplastic syndromes, we need to discuss several points. The first point is, does the patients really need an iron chelation agent? And for that, we have the number of transfusions the patient has received, potentially the ferritin levels of the patient, as well as the MRI when it’s available for the liver and for the heart. Based on that, we can decide, whether or not if the patient has really iron overload, if there is the need for some iron chelation. After that, we need to consider who is the patient and what are the potential comorbidities of the patient. For example, if the patient has some liver or kidney issues in the past—chronic kidney disease, cirrhosis—it can be a challenge to give iron chelation agents, such as deferasirox, for these patients. On the other hand, we have deferoxamine, which is a subQ IV formulation of iron chelation therapy. We know for this patient that the liver can be an issue, as well as thrombocytopenia. And we know that myelodysplastic syndromes can have some cytopenias. So, it’s maybe a challenge. Just based on the patient profile, we can potentially try to choose what is the better iron chelation agent that we can use.

Treatment of iron overload is something that is really important for a patient for which we’re seeing that survival may be prolonged, because we know that we need to have some time to have the accumulation of iron and to potentially have the consequences of the iron overload. It’s mostly with patients with lower-risk disease with transfusion-dependent anemia that we have to discuss the use of iron chelation agents. Basically, that’s a question that we should ask every patient with low-risk myelodysplastic syndromes.

The last patient I’ve seen for which we discussed the use, or not, of iron chelation agents was a 65-year-old lady with potentially years and years of life expectancy, but with recent diagnosis of transfusion-dependent myelodysplastic syndromes. And, for this moment, she does not qualify because she just had a couple of transfusions. One of the best treatments that we can give for iron overload is treatment that can modify as a disease evolution by itself, and stopping transfusion is one of the main goals that we should have. But when we need to have an iron chelation agent on the top of that, in that case, we need to wait a little bit until we begin to have some consequences of accumulation of iron compatible with potential tissue damage for the patient. In that case, we have several agents that we can use to potentially treat iron overload with. For example, over the last year, a switch from the subcutaneous or IV deferoxamine to the more recent oral agents like deferasirox.

Transcript Edited for Clarity

Transcript:

Vinod Pullarkat, MD: The decision to use an iron chelator in MDS is easier in a patient who has a lower-risk IPSS score because those patients are going to live longer. And if they’re transfusion-dependent, it is only a matter of time before iron overload sets in. The risk/benefit ratio in that patient favors iron chelation. Preventing iron overload in that patient would have important benefits with regard to long-term complications. If that patient was to require a stem cell transplant later on, the complications would be less. So, in that situation, although the patient may experience some side defects from the chelator itself, the benefits would clearly outweigh the risks.

In a higher-risk patient, we do not have enough data about the benefits of chelation. But, as more and more data accumulate, if there is a survival advantage and if there is delay in leukemic transformation, again, one could accept the risks of the treatment itself or the side effects if the survival is improved or if leukemic transformation is delayed. So, the important considerations would be the risk of the patient. Other comorbidities are important. For example, if you have renal dysfunction, using a chelator like deferasirox would obviously be difficult. And these patients often do have a lot of comorbidities. These are important considerations in deciding to use the drug.

Heather Leitch, MD, PhD: In terms of when to initiate iron chelation therapy, this is often dictated by the reimbursing authorities; for example, in British Columbia where I live. And their criteria are based on the data from congenital anemia. So, for example, a transfusion threshold of 20 red blood cell units, there’s a serum ferritin threshold of over 1000. I think we still have a lot to learn about MDS and whether these thresholds are appropriate. But what I will say is that in a substantial minority of patients, you may run into side effects that will limit the dose that you can give these patients. And so, whether it’s GI side effects or whether it’s an increase in creatinine levels, that can really limit the amount of iron that you can offload. I think that makes more sense moving forward and looking into the future to look at trying to use iron chelation therapy to prevent significant iron overload than trying to catch up with damaged tissue and organs.

Thomas Prebet, MD, PhD: When we assess the need for an iron chelation agent in patients with myelodysplastic syndromes, we need to discuss several points. The first point is, does the patients really need an iron chelation agent? And for that, we have the number of transfusions the patient has received, potentially the ferritin levels of the patient, as well as the MRI when it’s available for the liver and for the heart. Based on that, we can decide, whether or not if the patient has really iron overload, if there is the need for some iron chelation. After that, we need to consider who is the patient and what are the potential comorbidities of the patient. For example, if the patient has some liver or kidney issues in the past—chronic kidney disease, cirrhosis—it can be a challenge to give iron chelation agents, such as deferasirox, for these patients. On the other hand, we have deferoxamine, which is a subQ IV formulation of iron chelation therapy. We know for this patient that the liver can be an issue, as well as thrombocytopenia. And we know that myelodysplastic syndromes can have some cytopenias. So, it’s maybe a challenge. Just based on the patient profile, we can potentially try to choose what is the better iron chelation agent that we can use.

Treatment of iron overload is something that is really important for a patient for which we’re seeing that survival may be prolonged, because we know that we need to have some time to have the accumulation of iron and to potentially have the consequences of the iron overload. It’s mostly with patients with lower-risk disease with transfusion-dependent anemia that we have to discuss the use of iron chelation agents. Basically, that’s a question that we should ask every patient with low-risk myelodysplastic syndromes.

The last patient I’ve seen for which we discussed the use, or not, of iron chelation agents was a 65-year-old lady with potentially years and years of life expectancy, but with recent diagnosis of transfusion-dependent myelodysplastic syndromes. And, for this moment, she does not qualify because she just had a couple of transfusions. One of the best treatments that we can give for iron overload is treatment that can modify as a disease evolution by itself, and stopping transfusion is one of the main goals that we should have. But when we need to have an iron chelation agent on the top of that, in that case, we need to wait a little bit until we begin to have some consequences of accumulation of iron compatible with potential tissue damage for the patient. In that case, we have several agents that we can use to potentially treat iron overload with. For example, over the last year, a switch from the subcutaneous or IV deferoxamine to the more recent oral agents like deferasirox.